Iontophoresis device

ABSTRACT

An iontophoresis device useful for administering an ionic drug by iontophoresis has an iontophoresis electrode section (active electrode section) and a ground electrode section (inactive electrode section) both of which are to be connected to a power source. The iontophoresis device includes elements (members) of both of the electrode sections are all formed of membrane bodies, and includes ion exchange membranes different in ion selectivity, one being selective to ions of the same species as charged ions of the ionic drug and the other to ions different in species from the charged ions of the ionic drug that are arranged in the iontophoresis electrode section, and at least an ion exchange membrane selective to ions opposite to the charged ions of the ionic drug is arranged in the ground electrode section. The iontophoresis device can administer the ionic drug stably over a long period of time at high transport efficiency.

TECHNICAL FIELD

This invention relates to a device useful for transdermal administration(transdermal drug delivery) of various ionic drugs (ionic substanceshaving desired medicinal efficacy) by iontophoresis (hereinafter callediontophoresis device).

More specifically, this invention relates to an iontophoresis device ofhigh added value, which is constructed in such ways that aniontophoresis electrode section (active electrode section) and a groundelectrode section (inactive electrode section) are constructed to assurea stably energized state (constant current and/or constant voltage) overa long period of time, and that a drug (active) ingredient of an ionicdrug charged positive (+) or negative (−) at the iontophoresis electrodesection is efficiently carried (driven) toward the skin (or the mucosa).In other words, a high transference number (transference percentage) isassured, and that the iontophoresis electrode section (active electrodesection) and ground electrode section (inactive electrode section)contribute to the maintenance of the above-described stably energizedstate and prevent adverse effects to the skin, such as skin inflammationcaused by electrode reaction.

BACKGROUND ART

A method of introducing (delivering) ionic drug (ionic chemicalsubstance) placed at a desired part of the skin or mucosa (hereinaftersimply called the skin) into the body through the skin by giving theskin an electromotive force sufficient to drive such ionic drug iscalled iontophoresis (ion introduction method or ion delivery treatment)(See, for example, JP-A-63035266 for the above-mentioned definition ofiontophoresis).

As described above, iontophoresis performs desired medical treatment bydriving (carrying) an ionizable or ionic drug, which has been applied onthe skin, under predetermined electromotive force to deliver the sameinto the skin.

For example, positively charged ions are driven (carried) into the skinon the side of an anode in an electric system of an iontophoresisdevice.

Negatively charged ions, on the other hand, are driven (carried) intothe skin on the side of a cathode in the electric system of theiontophoresis device.

The following are examples of ionic drugs to which the above-describediontophoresis is applicable.

(1) Positively Chargeable Ionic Drugs:

Local anesthetic drugs (procaine hydrochloride, lidocaine hydrochloride,etc.), gastrointestinal drugs (calnitine chloride, etc.), skeletalmuscle relaxants (pancuronium bromide, etc.), and antibiotics(tetracycline derivatives, kanamycin derivatives, gentamicinderivatives).

(2) Negatively Chargeable Ionic Drugs:

Vitamins (hereinafter abbreviated as V) (VB₂, VB₁₂, VC, VE, folic acid,etc.), adrenocorticosteroids (hydrocortisone water soluble drugs,dexamethazone water soluble drugs, prednisolone water soluble drugs,etc.), and antibiotics (penicillins water soluble drugs, chloramphenicolwater soluble drugs).

Concerning methods for administering ionic drugs by iontophoresis anddevices to be used in the practice of such methods, research anddevelopment have been made for many years, and a variety of methods anddevices have been proposed.

Conventional art on this type of iontophoresis includes those using ionexchange membranes. The present invention also belongs to the categoryof technology using ion exchange membranes as will be described indetail below.

To facilitate understanding of the present invention that makes use ofion exchange membranes, a detailed description of typical examples ofthe prior art using ion exchange membranes will be given below.

1. Japanese Language Laid-open Publication (PCT) No. HEI 3-504343(International Publication No. WO90/04433), International PublicationDate: May 3, 1990 (Hereinafter Called the Prior Art 1):

-   -   (1) The prior art 1 discloses an iontophoresis electrode,        comprising (i) an electrode plate, (ii) a reservoir for storing        an ionic (or ionizable) drug to be delivered, and (iii) an ion        exchange membrane disposed on an outer side (skin-contacting        side) of the reservoir and selective to ions charged in the same        polarity as the ionic drug.    -   (2) In the prior art 1, the function of the ion exchange        membrane is described that, in the process of carrying (driving)        the ionic drug toward the skin, the ion exchange membrane        restricts movement of ions which are charged electrically        opposite to the ionic drug and move from the skin toward the        electrode plate. For example, it inhibits movement of ion        species existing on the skin such as sodium ions, chlorine ions        and other ions which may form an ionic current path different        from the current path formed by the ionic drug.

(3) The prior art 1 also describes that the efficiency of administrationof the ionic drug is increased because the ion exchange membrane reducesmigration of other mobile charge carriers into the reservoir containingthe ionic drug.

2. U.S. Pat. No. 4,722,726 (Hereinafter Called the Prior Art 2):

(1) The prior art 2 is referred to as a related art in the patentspecification of the prior art 1, and discloses an electrode of thefollowing construction:

(i) the electrode is divided into a first chamber containing anelectrolyte and a second chamber containing an ionized ingredient, and

(ii) the first chamber and the second chamber are isolated from eachother by an ion exchange membrane.

(2) The prior art 2 describes that the first chamber containing theelectrolyte can lessen the deleterious effects of hydrolysis of waterand that the ion exchange membrane can isolate the ionic drug from theelectrolyte in the first chamber.

However, the technology disclosed in the prior art 2, which useselectrolyte, also has an undesirable facet that the efficiency oftransport (transference number) of charged ions of the active ingredientin the ionic drug is apparently lowered, because it increases theconcentration of other additional ion species in the system.

Therefore, care should be taken in adopting a technology which useselectrolyte in this way.

3. JP-A-03094771 (Hereinafter Called the Prior Art 3):

(1) The prior art 3 discloses an electrode for iontophoresis comprising(i) a water retaining portion surrounded by a flexible supporting memberand having an electrode plate inside, (ii) an ion exchange membranedisposed on a front side (skin side) of the water-retaining portion, and(iii) a drug layer (ionic drug layer) disposed on a front side (skinside) of the ion exchange membrane.

(2) The prior art 3 is intended to administer an ionic drug of a highconcentration while preventing dilution of the drug with water in thecourse of administration of the drug.

(3) For this purpose, the prior art 3 discloses an iontophoresiselectrode having an ion exchange membrane which substantially inhibitspermeation of the drug but is water-permeable and a drug layer formed onthe body (skin) contacting side of the ion exchange membrane by adheringor depositing the drug by such methods as spray drying and spreading.

4. JP-A-04297277 (Hereinafter Called the Prior Art 4):

(1) The prior art 4 relates to the preceding Japanese patent applicationfiled by this applicant. In FIG. 2, for example, the prior art 4discloses an iontophoresis electrode section (active electrode section)(in FIG. 2, the negative electrode functions as an active electrodesection in relation to the polarity of ions of an ionic drug to beemployed) constructed in a multilayer structure of negative electrodeplate/gauze with the ionic drug contained therein/cation exchangemembrane/gauze with the ionic drug contained therein/anion exchangemembrane.

(2) The iontophoresis technology disclosed in the prior art 4 is thetechnology which has been improved by the present invention, and thelimitations of the prior art 4 will be discussed in detail when thepresent invention is described below.

As to the number of the ion exchange membrane(s) used (arranged) in theiontophoresis electrode section (active electrode section) in each priorart described above, the prior arts 1 through 3 disclose a single layerstructure using a single ion exchange membrane, while the prior art 4discloses a double layer structure using two ion exchange membranes. Inthis respect, the prior art 4 is different from the other prior arts 1through 3.

The present invention as will be described in detail below uses a doublelayer structure like the prior art 4. However, the present invention isbased on a technical concept totally different from prior art 4, as ithas distinct features that one or more ion exchange membranes are alsoarranged in the ground electrode section that ion exchange membranes arearranged as many as three or four in total in the iontophoresis device,and, moreover, that both electrode sections have been reconstructed soas to keep the transference number of charged drug ions at a high leveland significantly improve the ease (convenience) of handling.

As described above, use of ion exchange membrane(s) has been known intransdermal administration of an ionic drug by iontophoresis.

The above-described conventional iontophoresis technologies using one ormore ion exchange membranes, however, lacked a concept or idea ofpreventing or eliminating various drawbacks associated with anelectrochemical reaction on a surface of an electrode plate in theiontophoresis electrode section (active electrode section) and/or theground electrode section (inactive electrode section).

In other words, the conventional iontophoresis technologies using ionexchange membrane(s) lacked the concept of paying attention to allelectrochemical reactions at an iontophoresis electrode section (activeelectrode) and a ground electrode section (inactive electrode section)and of eliminating drawbacks caused by such reactions in order toestablish an iontophoresis technology of higher added value.

In the conventional iontophoresis technologies using ion exchangemembrane(s), more specifically, those of the above-described prior arts,one or more ion exchange membranes are used in an active electrodesection but no ion exchange membrane is employed in an inactiveelectrode section, and consequently they have the following drawbacks:

(i) It is difficult to administer an ionic drug (to perform drugdelivery) for a long period of time under stably energized conditions(it is difficult to keep it operating for a long period of time at aconstant voltage or constant current). For example, physiological salinewhich is an electrolyte solution (a solution containing an electrolytesubstance) is hydrolyzed to produce gas bubbles (oxygen gas, chlorinegas, etc.) on a surface of an electrode plate in an active electrodesection of positive (+) polarity, although the polarity of the activeelectrode section differs depending upon the polarity of charged ions ofan active ingredient in an ionic drug. Due to such gas bubbles, theelectric resistance increases, resulting in a substantial reduction inthe iontophoresis effect (the efficiency of transport of ions) withtime. This reduction also takes place by gas bubbles (hydrogen gas andthe like) produced at the ground electrode section of negative (−)polarity.

(ii) Burn, inflammation or the like (including electrical burn caused bya current itself or pH-induced burn caused by a sudden change in pH dueto H⁺ or OH⁻ produced by electrolysis) may occur on the skin at itssurface which is in contact with the active electrode section and/or theground electrode section.

(iii) The skin may be damaged at its surface, which is in contact withan electrode plate [for example□positive(+)□electrode] in the activeelectrode section, by a harmful substance formed through hydrolysis ofsweat on the skin surface and/or physiological saline as an electrolytesolution, for example, by hypochlorous acid (which is known as a strongoxidizing agent) produced based on Cl⁻ (chlorine ions) and as a resultof high acidification (production of HCl).

(iv) The skin may be damaged at its surface, which is in contact with anelectrode plate [for example, negative (−) electrode] in the groundelectrode section, by a harmful substance formed through hydrolysis ofsweat on the skin surface and/or physiological saline as an electrolytesolution, for example, as a result of high alkalinization (production ofNaOH).

DISCLOSURE OF THE INVENTION

The present inventors have already made some proposals for solving theabove-described drawbacks and limitations of the conventionaliontophoresis technologies which use ion exchange membrane(s) (seeJP-A-2000-229128), JP-A-2000-237326, and JP-A-2000-237328).

As compared to an iontophoresis electrode section (active electrodesection) comprising an iontophoresis electrode plate (active electrodeplate) connected to a power source of the same polarity as charged ionsof the active ingredient in the ionic drug, as disclosed, for example,in Japanese Language Laid-open Publication (PCT) No. HEI 3-504343 (theprior art 1), an ionic drug arranged on a front side of theiontophoresis electrode plate, and an ion exchange membrane arranged ona front side, that is, on a skin-contacting side of the ionic drug andselective to ions of the same ion species as the charged ions of theactive ingredient in the ionic drug, the iontophoresis devicespreviously proposed by the present inventors as mentioned above arebased on the finding that the above-described drawbacks associated withthe conventional iontophoresis electrode section (active electrodesection) can be solved by adopting the construction between theiontophoresis electrode plate and the ionic drug designed in such waysthat, with respect to the iontophoresis electrode plate,

(i) an electrolyte solution such as physiological saline is arranged atleast on the front side of the iontophoresis electrode plate, and

(ii) an ion exchange membrane selective to ions opposite to the chargedions of the active ingredient in the ionic drug is arranged on a frontside of the electrolyte solution.

Further, the iontophoresis devices previously proposed by the presentinventors as mentioned above are also based on the finding that theabove-described drawbacks associated with the conventional groundelectrode section (inactive electrode section) can be solved by adoptingthe construction designed in such ways that, with respect to theelectrode plate of the ground electrode section,

(iii) an electrolyte solution such as physiological saline is arrangedat least on a front side of the ground electrode plate, and

(iv) an ion exchange membrane selective to ions opposite to the chargedions of the active ingredient in the ionic drug is arranged on a frontside of the electrolyte solution, although it had not been known by thattime to arrange an ion exchange membrane on the side of a groundelectrode section (inactive electrode section).

However, the iontophoresis devices previously proposed by the presentinventors as mentioned above (see JP-A-2000-229128, JP-A-2000-237326,and JP-A-2000-237328) still have room for improvement when they areconsidered from the viewpoint of efficiency of delivery of an ionic druginto the skin, in other words, from the viewpoint of highly efficienttransport (transference number) of the ionic drug and also from theoperator's (user's) viewpoint of convenience (maintainability of thedevice, ease of parts replacement, and handling ease), although they areexcellent devices from the viewpoint of avoiding damage to the skincaused by electrochemical reactions at both of the electrode sections(the iontophoresis electrode section and the ground electrode section).

One objective of the present invention is, therefore, to provide aniontophoresis device of high added value, which assures a hightransference number in the transdermal delivery of an ionic drug andhighly increased convenience, on the basis of the iontophoresis devicespreviously proposed by the present inventors as mentioned above.

From the above-described viewpoints, the present inventors haveconducted a research with a view of providing the iontophoresis devicesas having been previously proposed by the present inventors with higheradded values. As a result, it has been found that a higher transferencenumber (high transference efficiency of ion species) and betterconvenience can be assured when:

(1) In the Iontophoresis Electrode Section,

(1)-1 the electrolyte solution to be arranged on the front side of theelectrode plate is formed into a membrane body by using a membrane whichhas ability of retaining the electrolyte solution in such a state thatthe membrane is impregnated with the electrolyte solution and also ofbeing electroconductive to ions (conductive to ions) in an electricfield, and

(1)-2 the ionic drug is also formed into a membrane body by using amembrane which has ability of retaining the ionic drug (drug solution)in such a state that the membrane is impregnated with the ionic drug andalso of being electroconductive to ions (conductive to ions) in anelectric field, and

(2) In the Ground Electrode Section,

(2)-1 the electrolyte solution to be arranged on the front side of theelectrode plate is formed into a membrane body by using a membrane whichhas ability of retaining the electrolyte solution in such a state thatthe membrane is impregnated with the electrolyte solution and also ofbeing electroconductive to ions (conductive to ions) in an electricfield.

The iontophoresis device according to the present invention has beenachieved based on the above-described findings.

The present invention can provide an iontophoresis device having highperformance (high transference number of ionic drugs), high convenience(maintainability of the device, ease in parts replacement, and handlingease), a compact construction, and high added value.

To describe briefly, the first aspect of the present invention relatesto an iontophoresis device useful for administering an ionic drug byiontophoresis, the iontophoresis device having an iontophoresiselectrode section (active electrode section) and a ground electrodesection (inactive electrode section) both of which are to be connectedto a power source, wherein:

(1) The Iontophoresis Electrode Section Comprises:

(1)-1. an electrode plate connected to a power source of the samepolarity as charged ions of the ionic drug,

(1)-2. an electrolyte-solution-retaining membrane arranged on a frontside of the electrode plate and retaining in it an electrolyte solutionin such a state that the membrane is impregnated with the electrolytesolution,

(1)-3. an ion exchange membrane arranged on a front side of theelectrolyte-solution-retaining membrane and selective to ions oppositeto the charged ions of the ionic drug,

(1)-4. an ionic-drug-retaining membrane arranged on a front side of theion exchange membrane and retaining the ionic drug in such a state thatthe membrane is impregnated with the ionic drug, and

(1)-5. an ion exchange membrane arranged on a front side of theionic-drug-retaining membrane and selective to ions of the same ionspecies as the charged ions of the ionic drug; and

(2) The Ground Electrode Section Comprises:

-   -   (2)-1. an electrode plate opposite in polarity to the electrode        plate in the iontophoresis electrode section,    -   (2)-2. an electrolyte-solution-retaining membrane arranged on a        front side of the electrode plate and retaining in it an        electrolyte solution in such a state that the membrane is        impregnated with the electrolyte solution, and    -   (2)-3. an ion exchange membrane arranged on a front side of the        electrolyte-solution-retaining membrane and selective to ions        opposite to the charged ions of the ionic drug.

The second aspect of the present invention relates to an iontophoresisdevice, which is a modification of the first aspect of the presentinvention, wherein:

(2) The Ground Electrode Section Comprises a Cation Exchange Membraneand an Anion Exchange Membrane in Combination, more specifically:

(2)-1. an electrode plate opposite in polarity to the electrode plate inthe iontophoresis electrode section,

(2)-2. an electrolyte-solution-retaining membrane arranged on a frontside of the electrode plate and retaining in it an electrolyte solutionin such a state that the membrane is impregnated with the electrolytesolution, and

(2)-3. an ion exchange membrane arranged on a front side of theelectrolyte-solution-retaining membrane and selective to ions of thesame ion species as the charged ions of the ionic drug,

(2)-4. an electrolyte-solution-retaining membrane arranged on a frontside of the ion exchange membrane and retaining in it an electrolytesolution in such a state that the membrane is impregnated with theelectrolyte solution, and

(2)-5. an ion exchange membrane arranged on a front side of theelectrolyte-solution-retaining membrane and selective to ions oppositeto the charged ions of the ionic drug.

In order to improve the performance of the iontophoresis device havingthe iontophoresis electrode section (active electrode section) and theground electrode section (inactive electrode section), the presentinvention features that:

(i) the electrolyte solutions in the iontophoresis electrode section andground electrode section are formed with solutions containing a readilyoxidizable or reducible substance, more specifically,

(ii) the electrolyte solutions in the iontophoresis electrode sectionand ground electrode section are formed with solutions containingferrous sulfate and ferric sulfate or an organic acid and/or its salt asa readily oxidizable or reducible substance.

To improve the convenience, such as handling ease (user friendliness),of the iontophoresis device, the present invention also relates to aiontophoresis device wherein

-   -   the elements (members) (1)-1 to (1)-5 or the elements (members)        (1)-2 to (1)-5 other than the electrode plate in the        iontophoresis electrode section are put together as an integral        unit to facilitate replacement of these elements (members), or    -   the elements (members) (2)-1 to (2)-3 or (2)-1 to (2)-5 or the        elements (members) (2)-2 to (2)-3 or (2)-2 to (2)-5 other than        the electrode plate in the ground electrode section are put        together as an integral unit to facilitate replacement of these        elements (members).

Other features of the iontophoresis device according to the presentinvention such as its small size and compact structure will be readilyunderstood by the following description of the technical construction ofthe present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view (overall perspective view) for describing the basicconstruction of an iontophoresis device (X) according to a firstembodiment of the present invention;

FIG. 2 is a fragmentary cross-sectional view of the iontophoresis device(X) according to the first embodiment of the present invention;

FIG. 3 is a basic construction diagram (fragmentary cross-sectionalview) of an iontophoresis electrode section (1) and a ground electrodesection (2) in the iontophoresis device (X) according to the firstembodiment of the present invention;

FIG. 4 is a diagram illustrating a modification of the iontophoresisdevice (X) shown in FIG. 3, specifically a modification of the groundelectrode section (2);

FIG. 5 is a diagram illustrating experimenting equipment equivalent tothe device (X) according to the first embodiment of the presentinvention;

FIG. 6 is a view illustrating an iontophoresis device (X) according to asecond embodiment of the present invention, and is a view correspondingto a small-diameter, cylindrical end section (1 a) in FIG. 2;

FIG. 7 is a view illustrating an iontophoresis device (X) according to athird embodiment of the present invention, and is a view correspondingto an end portion of the small-diameter, cylindrical end section (1 a)in FIG. 2;

FIG. 8 is a view (cross-sectional view) for illustrating aniontophoresis device (X) according to a fourth embodiment of the presentinvention; and

FIG. 9 is a front view of the iontophoresis device (X) according to thefourth embodiment of FIG. 8.

(Legend)

X . . . Iontophoresis device

1 . . . Iontophoresis electrode section

11 . . . Electrode plate

12 . . . Electrolyte-solution-retaining membrane

13 . . . Cation exchange membrane

14 . . . Ionic-drug (As⁻Na⁺)-retaining membrane

15 . . . Anion exchange membrane

2 . . . Ground electrode section

21 . . . Electrode plate

22 . . . Electrolyte-solution-retaining membrane

23 . . . Cation exchange membrane

24 . . . Electrolyte-solution-retaining membrane

25 . . . Anion exchange membrane

3 . . . Power source

31,32 . . . Cables

33 . . . Conductive spring member

4 . . . Skin

A . . . Skin-simulating bath

1 a . . . Small-diameter, cylindrical end section

1 b . . . Large-diameter, cylindrical grip section

BEST MODES FOR CARRYING OUT THE INVENTION

The following is a detailed description of the technical constructionand embodiments of the present invention.

In order to describe the technical construction of the presentinvention, the drawings will be referred to. Needless to say, it is tobe noted that the features shown in the drawings should be interpretedas merely illustrating the embodiments and also that the presentinvention is by no means limited to those of the drawings.

FIG. 1 to FIG. 3 are views illustrating the first embodiment of theiontophoresis device (X) according to the present invention.

FIG. 1 is the overall perspective view, while FIG. 2 is the fragmentarycross-sectional view. As shown in these drawings, the iontophoresisdevice (X) according to the present invention comprises, as mainelements (members), an iontophoresis electrode section (1), a groundelectrode section (2) and a power source (battery) (3).

FIG. 3 is the basic construction diagram (fragmentary cross-sectionalview) of both of the electrode sections, namely, the iontophoresiselectrode section (1) and the ground electrode section (2) whenadministration of an ionic drug is conducted under below-describedconditions by the iontophoresis device (X) according to the presentinvention as illustrated in FIG. 1 and FIG. 2.

The reference numeral (4) in FIG. 3 designates a site of the skin, andFIG. 3 also illustrates an administration method of an ionic drug (drugdelivery) by new iontophoresis which can be practiced by theiontophoresis device (X) according to the present invention.

(i) As the ionic drug, the sodium (Na) salt of ascorbic acid (vitaminC), which may hereinafter be abbreviated as As⁻Na⁺, is used. The ionicdrug is retained in an impregnatedly-retaining gel membrane (14) in sucha state that the gel membrane is impregnated with the ionic drug.

(ii) As the electrolyte solution, a 1:1 mixed aqueous solution of 1 Mlactic acid and 1 M sodium fumarate is used. This electrolyte solutionis retained in impregnatedly-retaining gel membranes (12,22) in such astate that the gel membranes are impregnated with the electrolytesolution.

(iii) As the types (in terms of ion selective permeability) of employedion exchange membranes, numerals 13 and 23 designate cation exchangemembranes while numeral 15 indicates an anion exchange membrane. Theseion exchange membranes are arranged as shown in the drawings.

(iv) An electrode plate (11) in the iontophoresis electrode section(active electrode section) is used as a negative (−) electrode.

(v) An electrode plate (21) in the ground electrode section (inactiveelectrode section) is used as a positive (+) electrode.

In FIG. 1 to FIG. 3, the reference numerals in these drawings correspondto the reference numerals of the individual elements of theiontophoresis device described above under the Means for Solving theProblems. For example, the element (1)-1 in the iontophoresis device (X)is designated as 11 in the drawings.

Most characteristic features of the iontophoresis device (X) accordingto the present invention are to provide an iontophoresis device of highadded value by increasing the quantity of ions migrated under givenelectromotive force, the quantity being well known to depend upon theconcentration, mobility and valence of ions, because the objective ofthis type of iontophoresis is to drive (deliver) an ionic drug into thebody through the skin (or mucosa) under predetermined electromotiveforce, in other words, by paying significant attention for theachievement of a high transference number and also by paying attentionto the elimination of factors of drawbacks (negative factors) such aselectrochemical reactions at the respective electrodes, specificallyskin inflammation due to the electrochemical reactions, and further bypaying attention for improvements in handling ease and convenience ofthe device.

In respect of the above-described objective that an ionic drug be driven(delivered) at a high transference number into the body, the prior artcannot be considered to have succeeded. In the present invention, a hightransference number (a high efficiency) can be stably achieved with theabove-described technical construction as will be described below.

It is also an important objective to eliminate drawbacks such as skininflammation, which are caused by electrochemical reactions occurringaround the electrodes in iontophoresis.

In iontophoresis, electrochemical reactions, specifically certainoxidizing reaction (positive electrode) and reducing reaction (negativeelectrode) unavoidably occur around the electrodes.

By the above-mentioned electrochemical reactions, formation of a harmfulsubstance through electrolysis of physiological saline as an electrolytesolution (for example, formation of hypochlorous acid from Cl⁻ at thepositive electrode, which is known as a strong oxidizing agent), suddenchanges in pH (sudden acidification at the positive electrode, suddenalkalization at the negative electrode) and production of gas bubbles(for example, H₂ gas at the negative electrode, O₂ gas and Cl₂ gas atthe positive electrode) occur, for example. These problems lead toserious drawbacks for the practice of iontophoresis, includingdeleterious effects on the human skin, skin irritations, incapability inenergization (due to an increase in resistance as a result of gasproduction), and the like.

In order to eliminate the drawbacks involved in the conventionaladministration methods of ionic drugs, such as above-described problemsregarding transference number and skin inflammation due toelectrochemical reactions, and also to improve the convenience of thedevice such as its handling ease, the iontophoresis device (X) accordingto the present invention has adopted, especially as the construction ofthe respective electrode sections, the construction that the individualelements (members) are constructed into layers as illustrated in FIG. 2and FIG. 3.

That is to say, the individual elements (members) (11 through 15) of theiontophoresis electrode section (1) and the individual elements(members) (21 through 23) of the ground electrode section (2) are allconstructed into layers such as plate members, membrane bodies and ionexchange membranes.

The properties of the membrane bodies, namely, the electrode plates,electrolyte-solution-retaining membranes, ionic-drug-retaining membrane,anion and cation exchange membranes in the present invention are set asdescribed above when As⁻Na⁺ is transdermally delivered as the ionicdrug.

The above-described features of the iontophoresis device (X) accordingto the present invention will hereinafter be described in more detail inthe case that sodium ascorbate (As⁻Na⁺) is transdermally delivered as anionic drug. In this case, charged ions of the active ingredient in theionic drug are obviously anions (As⁻).

Therefore, as illustrated in FIG. 3, the electrode plate (11) in theiontophoresis electrode section (1) is a negative (−) electrode whilethe electrode plate (21) in the ground electrode section (2) is apositive (+) electrode.

Needless to say that, when an ionic drug dissociates into positivelycharged ions, the polarities of the electrode plates (11,21) and thetypes (in terms of ion selective permeability) of the ion exchangemembranes (13, 15, 23) in the above-described electrode sections areopposite, respectively.

In FIG. 1 through FIG. 3 which illustrate the basic construction of theiontophoresis device (X) according to the first embodiment of thepresent invention, numeral 1 indicates the iontophoresis electrodesection (active electrode section), numeral 2 the ground electrodesection (inactive electrode section), numeral 3 the power source, andnumeral 4 the skin (or the mucosa).

As shown in FIG. 3, the iontophoresis electrode section (activeelectrode section)

(1) is constructed of:

(i) the negative (−) electrode plate (11),

(ii) the electrolyte-solution-retaining membrane (12) with theelectrolyte solution (1 M lactic acid/1 M sodium fumarate) retainedtherein in such a state that the membrane is impregnated with theelectrolyte solution,

(iii) the cation exchange membrane (13),

(iv) the ionic-drug-retaining membrane (14), and

(v) the anion exchange membrane (15).

As also illustrated in FIG. 3, the ground electrode section (2) isconstructed of:

(i) the positive (+) electrode plate (21),

(ii) the electrolyte-solution-retaining membrane (22) with theelectrolyte solution (1 M lactic acid/1 M sodium fumarate) retainedtherein in such a state that the membrane is impregnated with theelectrolyte solution, and

(iii) the cation exchange membrane (23).

In the present invention, the electrolyte-solution-retaining membranes(12,22) in both of the electrode sections (1,2) are not limited to thoseimpregnated with the above-mentioned electrolyte solution composed of 1M lactic acid and 1 M sodium fumarate as an electrolyte solution. Theymay also be made of those impregnated using physiological saline (forexample, 0.9% aqueous solution of NaCl) or those impregnated with acompound, which has an oxidation-reduction potential lower than theoxidation-reduction potential of water and can be more readily oxidizedor reduced compared with the electrolytic reaction of water (oxidizingand reducing reactions of water), as an electrolyte solution.

In the present invention, the electrolyte-solution-retaining membranes(12,22) in both of the electrode sections (1,2) may also be made ofmembranes retaining an ionic drug (for example, As⁻Na⁺ as mentionedabove) as a readily oxidizable or reducible compound in such a statethat the membranes are impregnated with the ionic drug, because, as anelectrolyte solution, the oxidation-reduction potential of the ionicdrug is generally lower than that of water. As such, ionic drugs areoxidized or reduced prior to the hydrolysis of water, the drawbackassociated with the hydrolysis of water can be eliminated.

Next, with reference to the basic construction diagrams (FIG. 1 to FIG.3) of the iontophoresis device (X) according to the present invention,the construction of a more specific iontophoresis device (X) forpracticing the new administration method of an ionic drug will bedescribed in the order of the specific construction of the iontophoresiselectrode section (active electrode section) (1) and the specificconstruction of the ground electrode section (inactive electrodesection) (2).

In the iontophoresis device (X) according to the present invention, theelectrode plate (11) in the iontophoresis electrode section (activeelectrode section) (1) can be composed of a desired electrode plate.Further, the electrode plate (21) in the ground electrode section(inactive electrode section) (2) can also be composed of a desiredelectrode plate.

For example, they can be composed of inert electrodes made of aconductive material such as carbon or platinum. Commercially-available,patch-type Red Dot™ monitoring electrodes (products of 3M Health CareLimited), which were used upon investigating possible reactions of theskin at both of the electrode sections (1,2) by using the iontophoresisdevice according to the present invention as will be describedsubsequently, are also useful.

In the iontophoresis device (X) according to the present invention,active electrodes known in the field of iontophoresis may also beadopted as the electrode plates (11,21) instead of the above-describedinert electrodes. When an active ingredient of an ionic drug becomespositive (+) ions, specifically when morphine hydrochloride or lithiumchloride is used as an ionic drug (in this case, morphine ions orlithium ions as a drug ingredient are positive ions, and chlorine ascounter ions are negative ions), illustrative of the above-mentionedactive electrodes are silver electrodes which react as positive (+)plates with these counter ions.

In the case of the above-described active electrodes, the silverelectrode readily reacts with chlorine ions (Cl⁻) so that insoluble AgClis formed in accordance with the formula: Ag+Cl⁻→AgCl+e⁻. An advantageavailable from the use of the above-described active electrodes residesin that the electrolytic reaction of water can be prevented because thestandard potential of the above reaction is lower than the standardpotential of the electrolytic reaction of water at the positive (+)electrode. It is, hence, possible to avoid sudden acidification based onH⁺ ions at the anode (positive electrode) and also sudden alkalizationbased on OH⁻ ions at the cathode (negative electrode).

In the iontophoresis device (X) according to the present invention,however, because plural, at least, three ion exchange membranesdifferent in ion selective permeability are used in the iontophoresissystem as described above and an insoluble substance (insoluble fineparticles) such as silver chloride (AgCl) formed at the active electrodemay impair the properties of the ion exchange membranes in someinstances, the care must be taken in their use.

As the iontophoresis device (X) according to the present invention usesthe plural ion exchange membranes different in ion selectivepermeability, it is preferred for the reason mentioned above to useinert electrodes instead of using more costly special electrodes such asactive electrodes.

The electrolyte-solution-retaining membrane (12) in the iontophoresiselectrode section (1) in the present invention is composed of a thinmembrane body with an electrolyte solution retained therein in such astate that the membrane is impregnated with the electrolyte solution. Asthis thin membrane body is of the same kind as a thin membrane bodyemployed as the below-described ionic-drug-retaining membrane with anionic drug retained therein in such a state that the membrane isimpregnated with the ionic drug and therefore, its details will bedescribed subsequently.

As the electrolyte solution, any desired electrolyte solution can beused. However, those which may cause trouble on the human skin throughelectrode reactions should be avoided.

For electrolyte solutions suitable in the present invention, organicacids and their salts, which exist in the human metabolic cycle, arepreferred from the viewpoint of harmlessness to the body.

For example, lactic acid, fumaric acid and the like are preferred.Specifically, an aqueous solution of 1 M lactic acid and 1 M sodiumfumarate (Na salt) at a ratio of 1:1 is preferred. This electrolytesolution is soluble relatively well in water, and allows a current toflow well through it. When a current is caused to flow as a constantcurrent, its electrical resistance is low, and no substantial pH changetakes place at the electrodes.

Examples of other electrolytes include:

(1) physiological saline (0.9% aqueous solution of NaCl), and

(2) a mixed aqueous solution of ferrous sulfate (FeSO₄) and ferricsulfate [Fe₂(SO₄)₃] (0.2 M:0.2 M equiratio aqueous solution).

In the case of the physiological saline, gas bubbles may be produced atboth of the negative and positive electrodes and may act as a resistanceto inhibit a constant-current power supply device as an accessory to theiontophoresis device (X), although the physiological saline has highconductivity. Further, since chlorine gas is produced from the positiveelectrode so that the solution tends to become acidic (formation ofHCl), full measures must, therefore, be taken to avoid damage to theskin.

In the case of the mixed aqueous solution of ferrous sulfate (FeSO₄) andferric sulfate [Fe₂(SO₄)₃], there are merits in that, when a current isapplied, resistance is low and occurrence of gas bubbles at theelectrodes is prevented, for reasons to be mentioned subsequentlyherein.

In such a case, to cope with a potential problem that the electrolytesolution may leak out in the course of manufacture of the iontophoresisdevice (X), it is necessary to take sufficient countermeasures, forexample, in connection with the corrosion resistance of the device,negative (undesirable) effects of sulfuric acid (deleterious substance)on the human body (skin).

The electrolyte solution kept in contact with the negative (−) electrodeplate (11) in the iontophoresis electrode section (1) in the presentinvention may preferably be composed of one including a readilyreducible compound.

On the other hand, the electrolyte solution kept in contact with thepositive (+) electrode plate (21) in the ground electrode section (2)according to the present invention may preferably be composed of oneincluding a readily oxidizable compound.

Needless to say, the positions of arrangement of the electrolytesolutions, in which the readily oxidizable compound and the readilyreducible compound are added, respectively, should be set correspondingto the electrochemical reactions at the respective electrode plates,namely, the reducing reaction at the negative (−) electrode and theoxidizing reaction at the positive (+) electrode.

In the present invention, the readily oxidizable and reducible compoundsadded to the electrolyte solutions, respectively, are preferably thoseexcellent in biosafety, economy (low price and good availability), etc.Illustrative are inorganic compounds such as ferrous sulfate and ferricsulfate; medicaments such as ascorbic acid (vitamin C) and sodiumascorbate; acidic compounds existing on the skin, such as lactic acid;and organic acids such as oxalic acid, malic acid, succinic acid andfumaric acid and/or salts thereof.

As is appreciated from the foregoing, the above-described equiratioaqueous solution of 1 M lactic acid and 1 M sodium fumarate is preferredas the electrolyte solutions.

In the case of a compound which is more readily oxidizable or reduciblethan the hydrolytic reaction of water (oxidation at the positiveelectrode and reduction at the negative electrode), for example, in thecase of ferric sulfate, ferric ions are readily reduced into ferrousions at the negative electrode. In the case of ferrous sulfate, on theother hand, ferrous ions are readily oxidized into ferric ions at thepositive electrode.

As a consequence, the drawbacks associated with the hydrolytic reactionof water can be eliminated. Coupled with the specific embodiments ofarrangement of the ion exchange membranes in the present invention, theiontophoresis device (X) having excellent performance is provided.

A detailed description will now be made about the merits available fromthe use of electrolyte solutions containing a readily oxidizablecompound or a readily reducible compound, respectively, as theelectrolyte solutions.

In the iontophoresis electrode section (1) and ground electrode section(2), electrochemical reactions take place so that the electrolytesolutions undergo dissociation. As a result, gas bubbles are produced inboth of the electrode sections (1,2) so that the electrode plates andtheir corresponding electrolyte solutions are prevented from contactingwith each other. For example, H₂ gas is produced at the negativeelectrode, and Cl₂ and O₂ gases are produced at the positive electrode.

If such a situation arises, the electric resistances of the electrodeplates (11,21) increase for the gas bubbles so that no current isallowed to flow no matter how much a voltage is raised. In the case ofthe above-described transdermal delivery of As⁻Na⁺, it is impossible tostably energize for a long time (30 minutes or longer). This is anextremely serious problem from the viewpoint of practical utility of theiontophoresis device (X).

To stably perform iontophoresis by eliminating the above-describedinstability factor, it is extremely important to inhibit production ofgas bubbles in the electrode plates (11,21).

To achieve this purpose, it is useful to add a substance, which issusceptible to an oxidizing or reducing reaction without producing gasbubbles, to both of the electrolyte solutions.

Described specifically, oxygen or hydrogen is produced when water isoxidized or reduced. To inhibit these reactions, ferrous sulfate, ferricsulfate, ascorbic acid or the sodium salt thereof is added as an exampleto the electrode compartment solutions (electrolyte solutions). Whensodium ascorbate is used, for example, sodium ascorbate is oxidativelydecomposed at the positive (+) electrode, where an oxidizing reactiontakes place, instead of production of oxygen. At the negative (−)electrode where a reducing reaction takes place, on the other hand,sodium ascorbate is reductively decomposed instead of occurrence ofhydrogen. As a consequence, it is possible to inhibit production ofoxygen or hydrogen gas bubbles which impair the stability ofenergization characteristics.

By sacrificially using a substance which is more readily oxidizable orreducible than water in an electrochemical reaction (a substance havingan oxidation-reduction potential lower than the oxidation-reductionpotential of water) such as sodium ascorbate as described above, theproduction of gas bubbles in both of the electrode sections (1,2) can beinhibited so that the iontophoresis device (X) can perform more stableoperation.

In addition to the above-described ferrous sulfate, ferric sulfate andascorbic acid, any substance can obviously be used as the sacrificialsubstance in the present invention insofar as it undergoes oxidation orreduction and inhibits the electrolytic reaction of water.

When sodium ascorbate is used as the sacrificial substance, sodiumascorbate changes into:

(i) CO₂, H₂CO₃ and the like at the electrode (negative electrode) wherea reducing reaction takes place, and

(ii) dehydroascorbic acid, 2,3-diketo-D-gulonic acid and the like at theelectrode (positive electrode) where an oxidizing reaction takes place.

The iontophoresis electrode section (1) in the present invention makesthe combined use of the cation exchange membrane (13) and the anionexchange membrane (15) as illustrated in FIG. 3.

As the cation exchange membrane (13) selective to ions opposite to theion species (As⁻) of the active ingredient in the iontophoretic drug(As⁻Na⁺) in the present invention, it is possible to use NEOSEPTA (CM-1,CM-2, CMX, CMS, CMB or the like) (product of TOKUYAMA CORPORATION).

As the anion exchange membrane (15) selective to ions of the same typeas the ion species (As⁻) of the active ingredient in the ionic drug(As⁻Na⁺) in the present invention, it is possible to use NEOSEPTA (AM-1,AM-3, AMX, AHA, ACH, ACS, ACS-3 or the like) (product of TOKUYAMACORPORATION).

The ionic drug (As⁻Na⁺) retaining membrane (14) in the iontophoresiselectrode section (1) in the present invention is composed of a thinmembrane body with the ionic drug retained therein in such a state thatthe membrane body is impregnated with the ionic drug.

In addition to sodium ascorbate (As⁻Na⁺) described above, conventionallyknown ionic drugs are usable in the present invention as the ionic drugwithout any limitations. Typical examples of this type of ionic drugsare as mentioned above.

In the present invention,

(1) the electrolyte-solution-retaining membrane (12) and

(2) the ionic-drug-retaining membrane (14)

are composed of thin membrane bodies with an electrolyte solution and anionic drug retained therein, respectively, in such a state that the thinmembrane bodies are impregnated with the electrolyte solution and theionic drug, respectively. As the thin membrane bodies, those of the samekind or of different kind can be selected for combined use from thinmembrane bodies to be described subsequently herein.

The thin membrane bodies will hereinafter be described in detail.

For the iontophoresis device (X), there are operation conditions(current value, voltage value) set from the viewpoint of safety to thehuman skin. The most important question, therefore, is how to achieveefficient transport of an ionic drug into the skin (transdermaldelivery), that is, to obtain a high transference number under theconditions which assure the safety. From this viewpoint, a descriptionwill be made about the thin membrane body, especially properties of theionic-drug-retaining membrane (14). In the present invention, for thethin membrane bodies for the electrolyte-solution-retaining membrane(12) in the iontophoresis electrode section (1) and theelectrolyte-solution-retaining membranes (22,24) in the below-describedground electrode section (2), the same kind of the thin membrane body asthat which makes up the ionic-drug-retaining membrane (14) is used.

In general, iontophoresis (transdermal delivery) is performed underconstant current conditions or constant voltage conditions. Adescription will hereinafter be made from the viewpoint of performingiontophoresis under constant current conditions, but the presentinvention is not limited to iontophoresis under such constant currentconditions.

In the present invention, operation conditions with the above-mentionedsafety of the iontophoresis device (X) taken into considerationcomprise:

(1) constant current conditions, specifically 0.1 to 0.5 mA, preferably0.1 to 0.3 mA, and

(2) voltage conditions which are suited to establish the above-describedconstant current and are safe, specifically below 50 V, preferably below30 V.

In order to efficiently deliver the ionic drug under the above-describedconditions, it is important for the thin membrane bodies to havesufficient ability to retain the ionic drug in such a state that thethin membrane bodies are impregnated with the ionic drug and also tohave sufficient ability to cause the impregnatedly retaining ionic drugto move toward the skin under the above-described electric fieldconditions, in other words, ability to cause ion species of theimpregnatedly retaining ionic drug to move toward the skin, and in stillother words, ion-electroconductive (ion-conductive) ability.

Under the above-described constant current conditions, theionic-drug-retaining membrane (thin membrane body) in the presentinvention should be equipped with desired impregnatedly-retainingability for the ionic drug and also with ability to cause ion species ofa desired active ingredient to move toward the skin (hereinafter calledion electroconductivity or ion conductivity).

As a result of many experiments, the present inventors found that a hightransference number (high drug-delivering ability) as great as 70 to80%, for example, can be obtained when the degree of impregnation of theionic-drug-retaining membrane (14) with a solution of the ionic drug isin a range of 30 to 40% in the layered construction of the membranebodies in the iontophoresis electrode section (1), in other words, inthe three-layer structure of the cation exchange membrane (13), theionic-drug-retaining membrane (14) and the anion exchange membrane (15).

The above-described degree of impregnation of 30 to 40% is a valueextremely close to the content of water in the cornea of the humaneyeball. They are, hence, in a surprising correlation.

Further, the above-described transference number of 70 to 80% is a valueof an extremely high level compared with those available from theconventional iontophoresis technologies.

Incidentally, the measurement of a degree of impregnation should beconducted immediately after impregnation to avoid time-dependentinfluence. Likewise, the measurement of a transference number should beconducted by arranging the ionic-drug-retaining membrane, which has beenimpregnated with the ionic drug, between the ion exchange membranes (13)and (15) while concurrently assembling the other members such thattime-dependent changes can be avoided as much as possible.

It should be noted that the above-described degree of impregnation withthe solution of the ionic drug and the transference number of the ionicdrug are used as indexes in the present invention. These are because noindex for objectively and totally evaluating the ability of the thinmembrane body to be impregnated with the ionic drug, the ability of thethin membrane to retain the ionic drug and the ability of the thinmembrane body to make ion species of the active ingredient in the ionicdrug, which is retained in the thin membrane body in such a state thatthe thin membrane body is impregnated with the ionic drug, to movetoward the skin (ability of ion electroconductivity or ionconductivity).

As other indexes which can be used as substitutes for the degree ofimpregnation and the transference number as indexes of the properties ofthe thin membrane body (the impregnatability, the retaining ability andthe ion conductivity), there are microporosity and transference number.

As the ionic-drug-retaining membrane (14) for use in the presentinvention, a hydrogel body of acrylic resin (acrylic hydrogel membrane)can be exemplified for its high biosafety, as typified by the use of theacrylic resin as contact lenses.

This acrylic hydrogel membrane is a gel body (of an intermediate formbetween liquid and solid) having a three-dimensional network structure(crosslinked structure), and a mixture obtained by adding water as adispersant and an electrolyte substance (NaCl or the like) to theacrylic hydrogel membrane allows a current to flow through it as aresult of migration of dissociated ions of the electrolyte substance. Inother words, the mixture obtained by impregnating the acrylic hydrogelmembrane (which can be considered to be a microporous gel membrane) withan aqueous solution of the electrolyte substance can be considered tobecome a high-molecular adhesive material equipped with ion conductivity(ion electroconductivity). This is because the acrylic hydrogel membranebecomes conductive to ions (electroconductive to ions) as a result ofpenetration of the dispersing medium and dissociated ion species intothe three-dimensional network of high-molecular chains in the acrylichydrogel membrane and migration of the ion species through the networkstructure in an electrical field.

The above-described correlation between the degree of impregnation ofthe acrylic hydrogel membrane and the transference number can be easilyadjusted by controlling the size of the three-dimensional networkstructure and the kinds and proportions of monomers making up the resin.

In the present invention, an acrylic hydrogel membrane having a degreeof impregnation of 30 to 40% and a transference number of 70 to 80% canbe prepared from 2-hydroxyethyl methacrylate and ethylene glycoldimethacrylate (monomer ratio: 98-99.5 to 0.5-2). Such acrylic hydrogelmembranes (microporous gel membranes) are available, for example, fromSun Contact Lens Co., Ltd. In the present invention, the degree ofimpregnation and the transference number have been confirmed to besubstantially the same within the usual thickness range of the acrylichydrogel membrane (microporous gel membrane) for use in the presentinvention, that is, in a range of from 0.1 mm to 1.0 mm.

As another ionic-drug-retaining membrane (14) for use in the presentinvention, there is a segmented polyurethane gel membrane (GELLODE™,product of Takiron Co., Ltd.).

This membrane is a segmented polyurethane gel membrane, which containspolyethylene glycol (PEG) and polypropylene glycol (PPG) as segments andhas been produced from these monomers and diisocyanate.

The segmented polyurethane gel membrane has a three-dimensionalstructure crosslinked by urethane bonds, and its degree of impregnation,transference number and adhesive force can be easily adjusted bycontrolling the size of openings in the network and the proportions ofthe monomers, as in the case of the above-described acrylic hydrogelmembrane.

In the segmented polyurethane gel membrane (microporous gel membrane)added with water as a dispersion medium and an electrolyte substance (analkali metal salt or the like), oxygen atoms of ether bonds in asegment-forming polyether and the alkali metal salt forms a complex and,when electricity is applied, an ion of the metal salt moves to theoxygen in the next void ether bond so that conductivity (ionelectroconductivity) is exhibited. Incidentally, the segmentedpolyurethane gel membrane (microporous gel membrane) is used as a gelpad for ultrasonic diagnostics by making use of its conductive (ionelectroconductive) property.

The segmented polyurethane gel membrane (microporous gel membrane) isfree of irritation to the skin and is a substance having high safety,because use of PEG-PPG-PEG copolymer, which make up the segments, as acosmetic ingredient has been approved.

As another ionic-drug-retaining membrane (14) for use in the presentinvention, an ion-conductive microporous sheet for the formation of agel-like solid electrolyte, for example, as a gel-like solid electrolytesheet in a solid cell (secondary cell) is useful.

Ion-conductive microporous sheets of this type are disclosed, forexample, in JP-A-11273452, and are basically formed of a microporouspolymer having a porosity of from 20 to 80% and composed primarily of anacrylonitrile polymer.

More specifically, the microporous polymer is an acrylonitrile copolymercomposed of 50 mole % or more (preferably 70 to 98 mole %) ofacrylonitrile and having a porosity of from 20 to 80%.

The acrylonitrile-based, gel-like solid electrolyte sheet (solid cell)is prepared by impregnating an acrylonitrile-based copolymer sheet,which is soluble in a non-aqueous solvent and has a porosity of 20 to80%, with an electrolyte-containing non-aqueous solvent to form thecopolymer sheet into a gel. Gel bodies include gel-like bodies and hardmembrane-like bodies.

From the viewpoints of ion conductivity, safety and the like, theacrylonitrile-based copolymer sheet soluble in the non-aqueous solventcan preferably be composed of an acrylonitrile/C₁-C₄ alkyl(meth)acrylate copolymer, acrylonitrile/vinyl acetate copolymer,acrylonitrile/styrene copolymer, acrylonitrile/vinylidene chloridecopolymer or the like. To form the copolymer sheet into a microporoussheet, conventional processes can be adopted including the wet (dry)paper making process, the needle punching process as a productionprocess of non-woven fabric, the water jet process, and formation of amelt-extruded sheet into a microporous body by stretching or solventextraction.

Among the ion-conductive microporous sheets of acrylonitrile-basedcopolymers employed in solid cells, gel bodies (including gel-likebodies and hard membrane bodies) each of which retains an ionic drug ina three-dimensional network of polymer chains and can achieve theabove-described degree of impregnation and transference number areuseful as thin membrane bodies, and each of which can serve as a basefor the ionic-drug-retaining membrane (14) in the present invention.

As to conditions under which the above-described thin membrane body(microporous gel membrane) is impregnated with the ionic drug or theelectrolyte solution in the present invention, optimal conditions can bedetermined from the viewpoint of a degree of impregnation, animpregnation speed and the like. For example, impregnation conditions of40□ and 30 minutes may be chosen.

In the present invention, various thin membrane bodies each of which isuseful as a base for the ionic-drug-retaining membrane (14) can be usedfor the thin membrane body which serves as a base for the electrolyteretaining membrane (12). These thin membrane bodies permit, in anelectrical field efficient migration of ion species dissociated in theelectrolyte solution with which the membrane body is impregnated.

Owing to the above-described technical construction of the iontophoresiselectrode section (1) of the iontophoresis device (X) according to thepresent invention, as compared to the transdermal delivery byconventional iontophoresis devices, the ionic drug can be transdermallydelivered stably over a longer period of time at a higher transferencenumber, and higher biosafety can be obtained.

Described specifically, owing to the above-described technicalconstruction of the iontophoresis electrode section (1), stableenergization properties can be obtained over a long period of time. Inother words, the ionic drug can be efficiently delivered into the bodystably for a long period of time through the skin (4) (drug delivery).It is also possible to prevent formation of a harmful substance throughelectrolysis in the electrode section, that is, to achieve a high levelof biosafety.

Next, with reference to FIG. 3, the construction of the ground electrodesection [positive (+) electrode] (2) of the iontophoresis device (X)according to the present invention will be described.

Up to the present, no iontophoresis technology which realizes stableenergization properties and biosafety has been proposed. This isprobably because the conventional technologies of iontophoresis weredeveloped under a simplistic concept of the construction of the groundelectrode section that it is arranged merely to establish grounding.

This observation is affirmed in view of Japanese Language Laid-openPublication (PCT) No. HEI 3-504343, JP-A-03094771 and JP-A-04197277 towhich this application is related, which were described above underBackground Art.

In addition to the above-described construction of the iontophoresiselectrode section (1) in the iontophoresis device (X), the presentinvention has also adopted, in relation to the overall construction ofthe device, a novel technical construction for the ground electrodesection (2), which is different from the conventional technicalconstruction, from the viewpoint of permitting stable administration ofan ionic drug for a long period of time at a high transference number(high efficiency) by iontophoresis and also obtaining a high level ofbiosafety.

As shown in FIG. 3, the ground electrode section (2) of theiontophoresis device (X) according to the present invention isconstructed of the electrode plate (21) of a polarity opposite to theelectrode plate (11) in the iontophoresis electrode section (1), theelectrolyte-solution-retaining membrane (22) arranged on the front sideof the electrode plate (21), and the ion exchange membrane (23) arrangedon the front side of the electrolyte-solution-retaining membrane (22),that is, on the side of the skin (4) and selective to ions opposite tocharged ions of the ionic drug.

It is a significant characteristic feature unseen in the prior art thatin the iontophoresis device (X) according to the present invention, theion exchange membrane (23) is indispensably arranged in the groundelectrode section (2) so as to heighten biosafety.

In the iontophoresis device (X) according to the present invention, theelectrolyte solution in the electrolyte-solution-retaining membrane (22)of the ground electrode section (2) may be composed of one containing asubstance, the oxidation-reduction potential of which is lower than theoxidation-reduction potential of water, like the above-describedelectrolyte solution in the electrolyte-solution-retaining membrane (12)of the iontophoresis electrode section (1), from the viewpoint ofbiosafety and stable operation for a long period of time. It is also asignificant feature that the iontophoresis device (X) is provided withhigh added value by arranging the ion exchange membrane (23) in theground electrode section (2) and also by forming the electrolytesolution with the above-described readily oxidizable or reduciblesubstance added therein.

As depicted in FIG. 3, in the first embodiment of the present invention,when an active ingredient of an ionic drug such as sodium ascorbate(As⁻Na⁺) is charged to negative (−), the electrode plate (21) in theground electrode section (2) of the iontophoresis device (X) becomespositive (+), the electrolyte solution in theelectrolyte-solution-retaining membrane (22) is composed of same 1:1mixed aqueous solution of 1M lactic acid and 1 M sodium fumarate as inthe iontophoresis electrode section (1), and the ion exchange membrane(23) is composed of a cation exchange membrane.

In the present invention, the electrolyte solution in theelectrolyte-solution-retaining membrane (22) of the ground electrodesection (2) can be composed of physiological saline which as mentionedabove, contains a readily oxidizable or reducible substance, forexample, ferric sulfate, ferric sulfate containing ferrous sulfate (anequimolar solution of both sulfates), ascorbic acid or sodium ascorbate.

The administration method of the ionic drug by iontophoresis, which wasexplained with reference to the iontophoresis device (X) shown in FIG.3, was in the case of sodium ascorbate (As⁻Na⁺) that the activeingredient of the ionic drug is charged negative (−) as described above.

Even when the active ingredient of an ionic drug is charged positive(+), it can be administered likewise in the present invention.

Examples of ionic drugs of this type whose active ingredients arecharged positive (+) include procaine hydrochloride and lidocainehydrochloride as local anesthetic drugs.

The polarities of the individual electrode plates (11,21) and the ionexchange properties of the ion exchange membranes (13,15,23) must bemade opposite in this case to the corresponding polarities and ionexchange properties in the above-described case in which sodiumascorbate (As⁻Na⁺) was administered.

When an ionic drug chargeable positive (+) is used as described above,the features of the present invention can be easily understood by makingan inference from the above-described case in which sodium ascorbatechargeable negative (−) was administered.

As the above-described power source (3) shown in FIG. 1 to FIG. 3, anypower source can be used as desired in the present invention.

In the present invention, a cell, a constant-voltage generator, aconstant-current generator (galvanostat), a constant-voltage andconstant-current generator, or the like can be used as the power source(3).

FIG. 4 shows the modification of the iontophoresis device (X) accordingto the first embodiment illustrated in FIG. 3, which specifically usestwo ion exchange membranes, i.e., a cation exchange membrane (23) and ananion exchange membrane (25) on the side of a ground electrode section(2).

In FIG. 4, reference numeral (24) indicates anelectrolyte-solution-retaining membrane which is similar to theelectrolyte-solution-retaining membrane (22) in the ground electrodesection (2) depicted in FIG. 3.

The modification illustrated in FIG. 4 is effective in preventing theskin troubles which may otherwise occur through the electrochemicalreaction on the side of the ground electrode section (2). Owing to thearrangement of the ion exchange membranes as illustrated in FIG. 4,specifically owing to the embodiment that the two ion exchange membranes(13,15) of different types are arranged on the side of the iontophoresiselectrode section (1) and the two ion exchange membranes (23,25) ofdifferent types are arranged on the side of the ground electrode section(2), only As⁻ are fed to the human skin (4) from the side of theiontophoresis electrode section (1), only Na⁺ are fed from the side ofthe ground electrode (2), and no other substances are practically fed.This modification, therefore, has extremely high biosafety.

EXAMPLES

<Experiment by Equivalent Experimenting Equipment>

Next, a description will be made on an experiment in which sodiumascorbate (As⁻Na⁺) was experimentally administered as an ionic drug byusing experimental equipment equivalent to the basic constructiondiagram of the iontophoresis device (X) as illustrated in FIG. 4.

By experiments and comparative experiments to be described subsequentlyherein, it will be appreciated that the iontophoresis device (X)according to the present invention can transdermally deliver an ionicdrug at an extremely high transference number or at high efficiency.

1. Experimenting Equipment

FIG. 5 is the schematic diagram of the experimenting equipmentequivalent to the iontophoresis device (X) shown in FIG. 4.

The reference numerals and letter of the experimenting equipment will beexplained as follows:

(1) Reference numerals 11, 12, 13, 14, 15, 21, 22, 23, 24 and 25 are thesame as in FIG. 3 to FIG. 4.

(2) The elements (11-12) in the iontophoresis electrode section (1) andthe elements (21-22) in the ground electrode section (2) wereconstructed by using platinum plates as the electrode plates, using a1:1 aqueous solution of 1 M lactic acid and 1 M sodium fumarate as anelectrolyte solution in both of the iontophoresis electrode section (1)and ground electrode section (2) and making the electrolyte solutionstirrable.

(3) As the cation exchange membranes (13,23) and anion exchangemembranes (15,25), NEOSEPTA CMS (cation) and NEOSEPTA AMX (anion)(products of TOKUYAMA CORPORATION) were used, respectively.

(4) As a thin membrane body for the ionic-drug-retaining membranedesignated at reference numeral (14), the above-described acrylichydrogel membrane (product of Sun Contact Lens Co., Ltd.) was used.

(5) As a thin membrane body for the electrolyte-solution-retainingmembrane designated at reference numeral (24), the above-describedacrylic hydrogel membrane (product of Sun Contact Lens Co., Ltd.) wasused, and as the electrolyte solution, a 0.9% aqueous solution of NaClwas used.

(6) Reference letter A designates a skin-simulating bath (chamber) whichsimulates the skin, and that bath was filled with a 0.9% aqueoussolution of NaCl.

Upon conducting an experiment, the elements (13 to 15) in theiontophoresis electrode section (1) and the elements (23 to 25) in theground electrode section (2) were put into integral structures,respectively, and assembled in the experiment equipment. In the presentinvention, the above-described formation of the members into theintegral structures can be effected by a conductive adhesive, heatsealing or the like.

2. Experimenting Conditions

1) Current value (constant current): 0.3 mA

2) Variations in voltage value (from the initial constant voltage values30V): 0.8 to 1.2 V

3) Energized time: 15 minutes to 35 minutes

3. Experimental Results and Discussion

The amount (micron mol) of ascorbic acid in the skin-simulating bath (A)subsequent to each predetermined energized time was investigated.

The results are presented below in Table 1.

1) It is appreciated from Table 1 that the amount of ascorbic acid thatreached the skin-simulating bath (A) increased with the energized time.

2) After energization at 0.3 mA for 35 minutes, the percent transferencewas found to be extremely high, that is, 80%.

(Note) The term transference number means a Hittorf number, and whichindicates the percentage of a current of specific ions, which isdetermined based on movement of specific ions, based on the wholecurrent flowing through an electrolyte solution. As the number of flowedelectrons is the same as the number of moved ions, the transferencenumber can be determined by calculating the quantity of electricity,namely, the number of electrons.

A theoretical calculation formula for the transference number isexpressed by:M (calculated value)=(I·t)/(F)

-   M: Molar number of flowed ions-   F (Faraday constant): 96500 C/-   I: Quantity of electricity (A: ampere)-   t: Energized time (seconds)

3) According to the experimental results under the operation conditions(current: 0.3 mA) set from the standpoint of biosafety (safety to theskin), transference numbers by the iontophoresis devices previouslyproposed by the present inventors [see JP-A-2000-229128,JP-A-2000-237326 and JP-A-2000-237328; And these previously proposediontophoresis devices lacked the idea that the elements (members) be allformed into thin membrane bodies] were as low as about 50% even after along time (45 minutes later), although the constant current was set at 1mA. The above-described transference number of 80% according to thepresent invention is, therefore, far superior.

4) The pH of the skin-simulating bath (A) was acidic (pH about 6.) atthe energized time of 0 minute, and remained substantially unchangedeven 35 minutes later. This is an advantageous effect which isattributed to the use of the ion exchange membranes on both electrodesections (1,2).

TABLE 1 Amount of ascorbic acid in the skin-simulating bath (A)Energized time 0 min 15 min 20 min 35 min Amount of ascorbic acid in the0.015 2.13 3.5 5.28 skin-simulating bath after energization (micron mol)<Experiments on the Skin>

Using an iontophoresis device (X) of the construction shown in FIG. 4,iontophoresis experiments (transdermal delivery experiments) wereactually conducted on the skin of animals and the skin of humanvolunteers. As base membranes for ionic-drug-retaining membranes andelectrolyte-solution-retaining membranes, the above-described acrylichydrogel membranes (microporous gel membranes) (products of the SunContact Lens Co., Ltd.) were used.

(1) Experimenting Equipment

An iontophoresis electrode section (1) connected to a galvanostat(constant-current generator) was constructed by bringing into closecontact an anion exchange membrane (15), an ionic-drug-retainingmembrane (14) impregnated with sodium ascorbate (100 mM), a cationexchange membrane (13), an electrolyte-solution-retaining membrane (12)impregnated with an electrolyte solution composed of an equiratiosolution of 1 M lactic acid and 1 M sodium fumarate, and an electrodeplate (11) in this order as viewed from the side of a skin-contactingsurface. On the other hand, a ground electrode section (2) wasconstructed by bringing into close contact a cation exchange membrane(23), an electrolyte-solution-retaining membrane (24) impregnated withthe above-described electrolyte solution, an anion exchange membrane(25), an electrolyte-solution-retaining membrane (22) impregnated withthe above-described electrolyte solution, and an electrode plate (21) inthis order as viewed from the side of a skin-contacting surface.

As the electrode plate (21) of the ground electrode section (2), apatch-type Red Dot monitoring electrode, commercial product, was used.Incidentally, this electrode also served to exhibit the function of theelectrolyte-solution-retaining membrane (22). Further, a conductive gel(Aquasonic 100, product of Parker Laboratories, Inc.) was coated on asurface of the ion exchange membrane (23), at said surface the groundelectrode section (2) to be brought into contact with the skin surface,to improve the conductivity.

(2) Experimenting Procedure

A color developer reagent, which intensifies the development of a colorwith time under the reducing action effect of ascorbic acid and causesprecipitation of formazan (red color), was intradermally injectedbeforehand. Depending upon the extent of color development, theiontophoresis effect on ascorbic acid was determined.

Employed as the color developer reagent was a solution prepared bydissolving 2,3,5-triphenyltetrazorium chloride (C₁₉H₁₅ClN₄; hereinafterabbreviated as TTC) at a concentration of 2% in a 0.9% aqueous solutionof NaCl. This color developer reagent has a property that, whensubjected to reducing action, it couples with two molecules of hydrogenand forms a formazan compound (vivid crimson) to change its color.

The current applied in this experiment was set at 0.3 mA (constantcurrent).

As a comparative experiment, on the other hand, ion non-exchange PPmembranes were used instead of the ion exchange membranes. The PPmembranes were polypropylene-made, microporous partitions (AN Filter,AN06, product of Nihon Millipore K.K.), and had no ion selectivepermeability.

(3) Experimental Results

The results are presented below in Table 2.

The ranking in Table 2 was made in accordance with the following system:

-   -   −: not reacted, ±: slightly reacted, +: apparently reacted, ++:        pronouncedly reacted.

TABLE 2 Chromogenic Energized time reaction Ascorbic acid adsministered15 min + (ion exchange membranes used) 20 min ++ 35 min ++ Control 15min − Ascorbic acid administered 20 min ± (PP membranes used) 35 min +

From those experiments, the following findings were obtained.

1) When the ion exchange membranes were used in accordance with theabove-described embodiment of the present invention, the colordevelopment reached the maximum in 20 minutes. When the ion nonexchangePP membranes were used in place of the ion exchange membranes, thereaction was observed as late as 35 minutes, and it was 60 minutes laterthat the color development reached the maximum value. The effectivenessof use of ion exchange membranes in accordance with the embodiment ofthe present invention was, therefore, proven on the skin of the body.

2) In the experiments, no skin alteration was observed at all on theside of the ground electrodes.

3) Variations in the applied voltage (initial voltages: 10 V) werewithin as small as about 1 V, although a current was applied at 0.3 mA,which falls within a current range safe for the body, for 35 minutes orlonger. This has proven that a 1:1 aqueous solution of 1 M lactic acidand 1 M sodium fumarate is useful as an electrolyte solution, and alsosuggests that, as lactic acid and fumaric acid are both organic acidsexisting in the body, use of physiological organic acids other thanlactic acid and fumaric acid is safe.

<Embodiment of Iontophoresis Device (Hardware Construction)>

Next, with reference to the drawings, a description will be made indetail about an embodiment of the iontophoresis device (X) according tothe present invention, which is useful for administering an ionic drugby iontophoresis, especially from the viewpoint of the elements of thedevice (equipment) (hardware construction).

In the drawings, some elements (members), connection modes of elements(members) themselves, or some hatching may be omitted in some instancesto clarify the illustration. Further, the thickness of each thinmembrane body does not represent the accurate thickness to improve theclarity of the illustration.

Nonetheless, the features omitted in the drawings can be readilyunderstood from the description of the individual embodiments and theaccompanying drawings.

FIG. 1 to FIG. 2 illustrate the first embodiment of the iontophoresisdevice (X) according to the present invention, in which FIG. 1 is theperspective view of the entire device and FIG. 2 is a partly cut-offcross-sectional view.

As shown in FIG. 1 to FIG. 2, the iontophoresis device (X) according tothe first embodiment of the present invention comprises the followingthree elements:

(i) the cylindrical iontophoresis electrode section (1),

(ii) the cylindrical ground electrode section (2) constructed as adiscrete (non-integral) unit relative to the cylindrical iontophoresiselectrode section (1), and

(iii) This constant current and constant voltage power source (3) mayhereinafter be called simply the power source (3).

In the iontophoresis device (X) according to the first embodiment of thepresent invention, the ground electrode section (2) is constructed as adiscrete unit relative to the iontophoresis electrode section (1). Theexpression constructed as a discrete unit as used above means that asillustrated in the drawings, the iontophoresis electrode section (1) andthe ground electrode section (2) are not integral. The iontophoresisdevice (X) has, for example, such a structure that an iontophoreticallytreated patient holds the ground electrode section (2) or brings theground electrode section (2) into contact with a desired skin surface,other than a treated site to establish grounding.

The iontophoresis device (X) according to the first embodiment of thepresent invention shown in FIG. 1 to FIG. 2 was constructed under thepremise that sodium ascorbate (As⁻Na⁺) is administered as an ionic drug.

Accordingly, the reference numerals of the respective elements (theelectrode plates, the electrolyte-solution-retaining membranes, theionic-drug-retaining membrane, and the ion exchange membranes) arrangedinside the iontophoresis device (X) shown in FIG. 1 to FIG. 2 indicatethe same elements described above with reference to FIG. 3.

The iontophoresis electrode section (1) in the iontophoresis device (X)according to the first embodiment of the present invention isconstructed of the following two elements as illustrated in FIG. 1 toFIG. 2:

(i) the non-conductive, small-diameter, cylindrical end section (1 a),and

(ii) the non-conductive, large-diameter, cylindrical grip section (1 b).

The end section (1 a) is constructed such that it can be detachablymounted on a front portion (1 b ₁) of the grip section (1 b), and withinthe end section (1 a), the elements designated by reference numerals (11to 15) are held or accommodated.

The elements (1 a,1 b) can be made of nonconductive plastics, forexample.

As illustrated in FIG. 2, the cylindrical end section (1 a) is composedof a front portion (1 a ₁), a main portion (1 a ₂), and a lock portion(1 a ₃) kept in engagement with the grip section (1 b). The frontportion (1 a ₁) has an opening (1 a ₁₁) and is constructed such that theanion exchange membrane (15) is exposed in the opening.

As also shown in FIG. 2, the cylindrical grip section (1 b), on theother hand, is composed of the front portion (1 b ₁), a main portion (1b ₂), and a rear end portion (1 b ₃). The front portion (1 b ₁) has anopening (1 b ₁₁) of substantially the same diameter as the main portion(1 a ₂) of the end section(1 a) and is constructed to define lock holes(1 b ₁₂) for guiding the lock portion (1 a ₃) such that the lock portion(1 a ₃) of the cylindrical end section (1 a) is locked on the frontportion (1 b ₁).

Further, the cylindrical grip section (1 b) is constructed to have aspring holding wall (1 b ₄) for fixedly supporting a spring member (33)accommodated within the cylindrical grip section (1 b) and made of aconductive material. The spring holding wall (1 b ₄) is constructed suchthat, as illustrated in FIG. 2, a free end of a cable (31) from thepower source (3) and the spring member (33) are electrically connected.

Detachable mutual locking of both of the elements (1 a,1 b) can beachieved by the lock portion (1 a ₃) of the cylindrical end section (1a) and the lock holes (1 b ₁₂) of the cylindrical grip section (1 b).Described specifically, the lock portion (1 a ₃) is inserted into thelock holes (1 b ₁₂), respectively, and the cylindrical end section (1 a)is turned clockwise or counterclockwise to lock them together.Incidentally, they are stably and detachably locked together becausespring force is exerted by the spring member (33) on the cylindrical endsection (1 a) (to urge the same).

The ground electrode section (2) in the iontophoresis device (X)according to the first embodiment of the present invention isconstructed of the following two elements as illustrated in FIG. 1 toFIG. 2:

(i) a non-conductive, small-diameter, cylindrical end section (2 a), and

(ii) a non-conductive, large-diameter, cylindrical main section (2 b).

Both of the elements (2 a,2 b) are constructed such that the end section(2 a) can be detachably mounted on the main section (2 b) by a similarmechanism as in the elements (1 a,1 b) in the iontophoresis electrodesection (1).

The elements (21,22,23) are accommodated inside the small-diameter,cylindrical end section (2 a) as depicted in FIG. 2. Further, aconductive spring member (34) is accommodated inside the large-diameter,cylindrical main section (2 b). An end portion of the spring member (34)is fixedly supported on a bottom part of the large-diameter, cylindricalmain section (2 b) and is also connected with an end portion of a cable(32) from the power source (3). Its opposite end portion, on the otherhand, urges the element (21), namely, the electrode plate (21) in theground electrode (2) under spring force, and also urges the cylindricalend section (2 a) under spring force such that the locking between thecylindrical end section (2 a) and the main section (2 b) can be assured.

As a modification of the iontophoresis device according to the firstembodiment of the present invention, the power source (3) may bereplaced by a cell, and this cell may be accommodated within theinternal space of the large-diameter, cylindrical grip section (1 b).

FIG. 6 is the view illustrating the second embodiment of theiontophoresis device according to the present invention, and correspondsto the small-diameter, cylindrical end section (1 a) in FIG. 2 whichpertains to the first embodiment.

The second embodiment adopts a different construction of thesmall-diameter cylindrical end section (1 a) from that of the firstembodiment (see FIG. 2), in which a small-diameter cylindrical endsection (1 a) is constructed to arrange a bottom cover (1 a ₄), which isequipped with a thread groove or slide guide grooves, on a rear end partof a main portion (1 a ₂) of the front end section (1 a). The mainportion (1 a ₂) is provided on an inner wall of the rear end partthereof with groove(s) corresponding to the thread groove or slide guidegrooves in the bottom cover (1 a ₄), and by these grooves, the bottomcover (1 a ₄) is fixed to the main portion (1 a ₂). In this embodiment,the urging force applied by the spring member (33) can be adjusted.

FIG. 7 is the view illustrating the third embodiment of theiontophoresis device according to the present invention, and correspondsto the front part of the small-diameter, cylindrical end section (1 a)in FIG. 2 which pertains to the first embodiment.

A characteristic feature of the third embodiment is that anionic-drug-retaining membrane (14) is extended outward so as to form aconcentric circular part as well beyond the outer circumference of acircular anion exchange membrane (15).

In this case, use of a gel membrane having good adhesion to the skin,for example, GELLODE (trade name, product of Takiron Co., Ltd.),specifically the segmented polyurethane gel membrane having PEG-PPGsegments or the like as a membrane (microporous gel membrane), whichserves as a base of the ionic-drug-retaining membrane (14), has a meritin that adhesion of the anion exchange membrane (15) to the skin surfacecan be assured.

Although the third embodiment is a modification of the above-describedfirst embodiment, it can be used as a modification of the secondembodiment.

FIG. 8 to FIG. 9 illustrate the iontophoresis device (X) according tothe fourth embodiment of the present invention, in which FIG. 8 is itscross-sectional view and FIG. 9 is its front view.

In an elongated iontophoresis electrode section (1) in this fourthembodiment, an elongated, cylindrical main section (1 b) serves as agrip section, and the above-described elements (11 to 15), spring member(33) and power source (3) are accommodated inside the main section (1b).

A ground electrode section (2), on the other hand, is constructed insubstantially the same structure as the cylindrical end section (1 a) inthe second embodiment (see FIG. 6). The elements (21 to 23) accommodatedinside the cylindrical end section (1 a) of the ground electrode section(2) are different from the elements (11 to 15) in the second embodimentbecause this part becomes the ground electrode section (2) in the fourthembodiment.

In the fourth embodiment, the operator (user) of the iontophoresisdevice (X) is no longer required to establish grounding by holding theground electrode section (2), unlike the first to third embodiments, andtherefore, the fourth embodiment brings about improved convenience.

Further, the ground electrode section (2) can effectively establishgrounding because it is arranged at a position close to theiontophoresis electrode section (1).

I. Advantageous Effects

According to the present invention, excellent advantageous effects canbe brought about as will be described next:

(i) In the iontophoresis electrode section (active electrode section)and the ground electrode section (inactive electrode section),especially the ionic drug and electrolytic solutions are retained inspecific, impregnatedly-retaining membranes, and ion exchange membraneshaving different ion selectivity are arranged in a specific order. Underthe above-described specific construction, a stably energized state(constant current and/or constant voltage) can be maintained for a longperiod of time. In the iontophoresis electrode section, the activeingredient of the ionic drug, said active ingredient being chargedpositive (+) or negative (−), can be delivered (drug delivery)efficiently at a high transference number to the skin (or the mucosa).

(ii) The iontophoresis electrode section (active electrode section) andthe ground electrode section contribute to the maintenance of theabove-described stable energized state for a long period of time, andthe use (arrangement) of particular ion exchange membranes on the bothelectrode sections can eliminate the deleterious effects on the skinthrough electrode reactions.

(iii) In the iontophoresis electrode section (active electrode section)and the ground electrode section, the elements relevant to the deliveryof ions are all formed into thin membrane bodies, including theelectrode plates. The device is, therefore, provided with significantimprovements in convenience such as compactness, maintenability, andhandling ease (including ease in replacing members).

(iv) In the iontophoresis device according to the present invention,some of the individual elements (members) which make up the electrodesections (active electrode section and ground electrode section),specifically the electrode plates, electrolyte-solution-retainingmembranes, ionic-drug-retaining membrane and ion (cation and anion)exchange membranes can be assembled into kits beforehand. Depending onthe various therapeutic purposes, membrane bodies retaining desired drugsolutions or drug solutions of desired concentrations in such a statethat the membrane bodies are impregnated with the desired drug solutionsor the drug solutions of the desired concentrations, can be preparedinto kits beforehand. Upon using the iontophoresis device, an operator(user) can select desired ones of the kits, depending upon thetherapeutic purpose and can assemble them easily. This leads tosignificant improvements in the convenience of the device.

In addition, the subassembly into such kits makes it possible to achievea reduction in the size of the device, prevention of treatment errors(because the elements have been sub-assembled into kits), or the like.

INDUSTRIAL APPLICABILITY

The iontophoresis device according to the present invention cantransdermally deliver an ionic drug at high efficiency under stableenergized conditions for a long period of time.

The iontophoresis device according to the present invention is alsoexcellent in safety, because ion exchange membranes are arranged on theside of the active electrode section and also on the side of the groundelectrode section not only from the viewpoint of transference number ofthe ionic drug but also from the viewpoint of assuring high safety tothe skin.

In the iontophoresis device according to the present invention, both ofthe electrode sections are constructed of thin membrane bodies in theirentirety. Subassembly or the like of these thin membrane bodies intokits is effective for forming the device into a smaller size and alsofor making the device excellent in ease in replacing its members(parts), in preventing treatment errors and also in handling.

Although iontophoresis treatments of this type have been proposed theiontophoresis device according to the present invention equipped withvarious meritorious characteristics as mentioned above, is a reallypractical device, and its industrial value is significant.

1. An iontophoresis device useful for administering an ionic drug byiontophoresis, said iontophoresis device having an iontophoresiselectrode section (active electrode section) and a ground electrodesection (inactive electrode section) both of which are connected to apower source, comprising (1) said iontophoresis electrode sectioncomprises: (1)-1. an electrode plate connected to said power source ofthe same polarity as the charged ions of said ionic drug, (1)-2. anelectrolyte-solution-retaining membrane arranged on a front side of saidelectrode plate and retaining therein an electrolyte solution in such astate that said electrolyte-solution-retaining membrane is impregnatedwith said electrolyte solution, (1)-3. an ion exchange membrane arrangedon a front side of said electrolyte-solution-retaining membrane andselective to ions opposite in polarity to said charged ions of saidionic drug, (1)-4. an ionic-drug-retaining membrane arranged on a frontside of said ion exchange membrane and retaining therein said ionic drugin such a state that said ionic-drug-retaining membrane is impregnatedwith said ionic drug, and (1)-5. an ion-exchange membrane arranged on afront side of said ionic-drug-retaining membrane and selective to ionsof the same species as said charged ions of said ionic drug; and (2)said ground electrode section comprises: (2)-1. an electrode plateopposite in polarity to said electrode plate in said iontophoresiselectrode section, (2)-2. an electrolyte-solution-retaining membranearranged on a front side of said electrode plate and retaining thereinan electrolyte solution in such a state that saidelectrolyte-solution-retaining membrane is impregnated with saidelectrolyte solution, and (2)-3. an ion exchange membrane arranged on afront side of said electrolyte-solution-retaining membrane and selectiveto ions opposite in polarity to said charged ions of said ionic drug,wherein two said electrolyte-solution-retaining membranes in both saidintrophoresis and ground electrode sections retain therein anelectrolyte solution containing one or more compounds which have anoxidation-reduction potential lower than the oxidation-reductionpotential of water in electrolysis in such a state that two saidelectrolyte-solution-retaining membranes are impregnated with saidelectrolyte solution, and said electrolyte solution contains (1) lacticacid and sodium fumarate, or (2) ferrous sulfate and ferric sulfate. 2.The iontophoresis device according to claim 1, wherein: (2) said groundelectrode section comprises: (2)-1. an electrode plate opposite inpolarity to said electrode plate in said iontophoresis electrodesection, (2)-2. an electrolyte-solution-retaining membrane arranged on afront side of said electrode plate and retaining therein an electrolytesolution in such a state that said electrolyte-solution-retainingmembrane is impregnated with said electrolyte solution, (2)-5. an ionexchange membrane arranged on a front side of saidelectrolyte-solution-retaining membrane and selective to ions of thesame species as said charged ions of said ionic drug, (2)-4. anelectrolyte-solution-retaining membrane arranged on a front side of saidion exchange membrane and retaining therein an electrolyte solution insuch a state that said electrolyte-solution-retaining membrane isimpregnated with said electrolyte solution, and (2)-3. an ion exchangemembrane arranged on a front side of said electrolyte-solution-retainingmembrane and selective to ions opposite in polarity to said charged ionsof said ionic drug, wherein three said electrolyte-solution-retainingmembranes in both said introphoresis and ground electrode sectionsretain therein an electrolyte solution containing one or more compoundswhich have an oxidation-reduction potential lower than theoxidation-reduction potential of water in electrolysis in such a statethat three said electrolyte-solution-retaining membranes are impregnatedwith said electrolyte solution, and said electrolyte solution contains(1) lactic acid and sodium fumarate, or (2) ferrous sulfate and ferricsulfate.
 3. The iontophoresis device according to claim 1, wherein saidiontophoresis electrode section is constructed of assembling elements,comprising of said electrode plate, said electrolyte-solution-retainingmembrane, said ionic-drug-retaining membrane, and said two ion exchangemembranes, some or all of which have been assembled into one or morekits beforehand.
 4. The iontophoresis device according to claim 3,wherein said electrode plate and said electrolyte-solution-retainingmembrane of said assembling elements have been assembled into a kitbeforehand.
 5. The iontophoresis device according to claim 3, whereinsaid ionic-drug-retaining membrane and two said ion exchange membranesof said assembling elements have been assembled into a kit beforehand.6. The iontophoresis device according to claim 1, wherein said groundelectrode section is constructed of assembling elements, comprising ofsaid electrode plate, said electrolyte-solution-retaining membrane andsaid ion exchange membrane, some or all of which have been assembledinto one or more kits beforehand.
 7. The iontophoresis device accordingto claim 6, wherein said electrode plate and saidelectrolyte-solution-retaining membrane of said assembling elements havebeen assembled into a kit beforehand.
 8. The iontophoresis deviceaccording to claim 6, wherein said electrode plate, saidelectrolyte-solution-retaining membrane and said ion exchange membraneof said assembling elements have been assembled into a kit beforehand.9. The iontophoresis device according to claim 1, wherein-two saidelectrolyte-solution-retaining membranes in both said introphoresis andground electrode sections and said ionic-drug-retaining membrane in saidiontophoresis electrode section comprise of an acrylic hydrogel membranehaving a degree of impregnation of 30 to 40%.
 10. The iontophoresisdevice according to claim 1, wherein said iontophoresis electrodesection and said ground electrode section are constructed into discreteunits.
 11. The iontophoresis device according to claim 1, wherein saidiontophoresis electrode section and said ground electrode section areconstructed into an integral structure.
 12. The iontophoresis deviceaccording to claim 2, wherein said iontophoresis electrode section isconstructed of assembling elements, comprising of said electrode plate,said electrolyte-solution-retaining membrane, said ionic-drug-retainingmembrane, and two said ion exchange membranes, some or all of which havebeen assembled into one or more kits beforehand.
 13. The iontophoresisdevice according to claim 12, wherein said electrode plate and saidelectrolyte-solution-retaining membrane of said assembling elements havebeen assembled into a kit beforehand.
 14. The iontophoresis deviceaccording to claim 12, wherein said ionic-drug-retaining membrane andtwo said ion exchange membranes of said assembling elements have beenassembled into a kit beforehand.
 15. The iontophoresis device accordingto claim 2, wherein said ground electrode section is constructed ofassembling elements, comprising of said electrode plate, two saidelectrolyte-solution-retaining membranes, and two said ion exchangemembranes, some or all of which have been assembled into one or morekits beforehand.
 16. The iontophoresis device according to claim 15,wherein said electrode plate and said electrolyte-solution-retainingmembrane, arranged on a front side of said electrode plate, of saidassembling elements have been assembled into a kit beforehand.
 17. Theiontophoresis device according to claim 15, wherein two said ionexchange membranes and said electrolyte-solution-retaining membranedisposed between two said ion exchange membranes of said assemblingelements have been assembled into a kit beforehand.
 18. Theiontophoresis device according to claim 2, wherein three saidelectrolyte-solution-retaining membranes in both said introphoresis andground electrode sections and said ionic-drug-retaining membrane in saidiontophoresis electrode section comprise of an acrylic hydrogel membranehaving a degree of impregnation of 30 to 40%.
 19. The iontophoresisdevice according to claim 2, wherein said iontophoresis electrodesection and said ground electrode section are constructed into discreteunits.
 20. The iontophoresis device according to claim 2, wherein saidiontophoresis electrode section and said ground electrode section areconstructed into an integral structure.